Molecular umbrellas represent a unique class of amphiphiles that has proven capable of transporting certain hydrophilic peptides across phospholipid bilayers without damaging the integrity of the membrane. Very recently, molecular umbrellas have also been found capable of (i) transporting a 16-mer oligonucleotide across cholesterol-rich phospholipid bilayers, (ii) increasing the water- solubility and hydrolytic stability of a hydrophobic drug, and inhibiting the binding of HIV and HSV to mammalian cells. The specific aims of this research build upon these latest findings. In particular, this research is intended to provide a framework of understanding (i.e., to develop the basic science) that will allow for the rational exploitation of these findings. Specifically, the goals of this research are aimed at (i) clarifying how the overall length of a molecular umbrella, the spacing between facially amphiphilic units and an attached oligonucleotide, its shielding capacity, the degree of facial hydrophilicity, and the presence of facial guanidinium group affect its ability to transport an oligonucleotide across cholesterol-rich phospholipid bilayers, (ii) testing the feasibility of creating molecular umbrella conjugates of Amphotericin B that exhibit high critical micelle concentrations, high hydrolytic stability and high membrane selectivity, and (iii) defining the consequences of the size of persulfated molecular umbrellas on bilayer transport and on antiviral activity. The long-term objective of this program is to devise fundamentally new approaches to drug delivery based the use of molecular umbrellas. RELEVANCE: One of the major challenges in medicinal chemistry is to find ways of transporting drugs, effectively, into cells so that they can reach their intended target without damaging the integrity of the membrane. In particular, the outer "skin" of cells has proven to be a significant barrier that has limited the access of many water-soluble drugs. This research is aimed at finding a general solution to this problem by designing molecules that can carry drugs across such barriers. This research has the potential for leading to new and more effective drugs that could be used to treat a wide range of diseases;e.g., cancer, HIV, Herpes virus and fungal infections.